Tau promotes neurodegeneration through global chromatin relaxation

Abstract

The microtubule-associated protein tau is involved in a number of neurodegenerative disorders, including Alzheimer’s disease (AD). Previous studies link oxidative stress and subsequent DNA damage to neuronal death in AD and related tauopathies. Since DNA damage can significantly alter chromatin structure, we examined epigenetic changes in tau-induced neurodegeneration. We have found widespread loss of heterochromatin in tau transgenic Drosophila and mice, and in human AD. Importantly, genetic rescue of tau-induced heterochromatin loss substantially reduced neurodegeneration in Drosophila. We identified oxidative stress and subsequent DNA damage as a mechanistic link between transgenic tau expression and heterochromatin relaxation, and found that heterochromatin loss permits aberrant gene expression in tauopathies. Furthermore, large-scale analyses from human AD brains revealed a widespread transcriptional increase in genes that are heterochromatically silenced in controls. Our results establish heterochromatin loss as a toxic effector of tau-induced neurodegeneration, and identify chromatin structure as a potential therapeutic target in AD.